P351: DOSE-ADJUSTED EPOCH + INOTUZUMAB OZOGAMICIN (DA-EPOCH-INO) IS SAFE AND ACTIVE IN ADULTS WITH RELAPSED/REFRACTORY (R/R) B LYMPHOBLASTIC LEUKEMIA (B-ALL): INITIAL RESULTS OF A PHASE I TRIAL
Authors: R. Cassaday, K.-L. Garcia, T. Gooley, C. Martino, M.-E. Percival, A. Halpern, V. Oehler, J. Abkowitz, R. Walter, C. Ghiuzeli, E. Estey
Journal: HemaSphere (2022)

Background: Despite new drugs, survival with R/R B-ALL remains poor. Combination therapies may improve outcomes, but none are proven superior, and toxicities may pose limits. InO has been added to low-intensity chemotherapy, but the risks/benefits of such combinations are poorly defined. As we recently found DA-EPOCH to be effective for untreated ALL, we here tested the addition of InO to DA-EPOCH (#NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible adults had R/R CD22+ B-ALL with ≥5% blasts in blood/marrow or ≥1 site of extramedullary disease [EMD] ≥1.5 cm in diameter. No history of sinusoidal obstructive syndrome (SOS) or chronic liver disease was allowed. Other key eligibility criteria included bilirubin ≤1.5x upper limit of normal (ULN), AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN, QTc ≤500 msec, and ECOG 0-2. All patients (pts) gave written informed consent. DA-EPOCH was given on Days 1-5 with G-CSF. Three dose levels (DL) of InO given on Days 8 and 15 were studied in 28-day cycles: DL1, 0.3 and 0.3 mg/m2; DL2, 0.6 and 0.3 mg/m2; and DL3, 0.6 and 0.6 mg/m2 (respectively). In Cycles 2+, EPOCH was dose-adjusted based on the hematologic nadir from the prior cycle. Up to 4 cycles were permitted. Hepatic prophylaxis with ursodiol and CNS-directed therapy with intrathecal chemotherapy was recommended. MTD was the dose of InO yielding a true dose-limiting toxicity (DLT) rate of 33%. Initial dose-escalation plan for InO was a 6 + 6 design, but after 5 pts enrolled, this was modified to Bayesian Optimal Interval Design (BOIN) with target accrual of 24 pts. Secondary objectives were descriptions of treatment-related adverse events (TRAEs) per NCI CTCAE v5; efficacy by rate of complete remission without or with incomplete hematologic recovery (CR/CRi) and response at EMD sites per NCCN; measurable residual disease negativity (MRD-) by multiparameter flow cytometry (MFC) and high-throughput sequencing (HTS; clonoSEQ) of bone marrow aspirate; and survival. Results: To date, 17 pts have been enrolled (Table). All are evaluable for DLT. 5 pts were treated at DL1; then per BOIN, 3 pts at DL2, and 9 pts at DL3. Median number of cycles given was 2 (range, 1-3). There have been 4 DLTs: 1 at DL2 (20%; grade 4 sepsis) and 3 at DL3 (33%; grade 4 hyponatremia, grade 4 SOS, and prolonged pancytopenia). The single case (6%) of SOS occurred after allografting and is ongoing. There have been no treatment-related deaths. Grade 3+ non-heme TRAEs were seen in 13 pts (76%). Those seen in >1 pt were infections (5 pts; 8 events), neutropenic fever (5 pts; 5 events), oral mucositis (3 pts; 4 events), and increased ALT (2 pts; 3 events); all these events resolved. Other hepatic toxicity was generally mild. Of 10 pts who received ≥2 cycles, 5 (50%) escalated the dosing of EPOCH, while 2 (20%) de-escalated. 17 pts are evaluable for response. Of 13 with >5% blasts, 12 (92%; 90% confidence interval 68-100%) achieved CR/CRi, 10 (77%) after 1 cycle. MRD- by MFC was achieved in 9 (75%); 1 had prior InO. In the 5 pts with EMD, 4 (80%) responded including 3 CRs. To date, 6 pts (35%) have undergone allograft post-study. Median follow-up of survivors is 7 mo, with 7 pts in ongoing remission beyond 6 mo. Image:Summary/Conclusion: DA-EPOCH-InO has a manageable toxicity profile with infrequent DLTs and only 1 case of SOS in heavily pre-treated adults with B-ALL. Nearly all pts with >5% blasts at enrollment achieved CR, with most being MRD- by MFC. Responses in EMD were common. Enrollment is ongoing. Updated follow-up and responses by HTS will be presented.